Abstract
Objective: Phenytoin displays nonlinear pharmacokinetics due to the saturation of its’ metabolizing enzymes, thus making dosing adjustments a challenge in clinical practice. However, data on the pharmacokinetic parameters of phenytoin in pediatric patients with epilepsy in Thailand remain lacking. This study aimed to determine the pharmacokinetic parameters of phenytoin, and the factors influencing them in epileptic Thai children using therapeutic drug monitoring data.
 Methods: Steady state phenytoin plasma concentrations were collected from 96 Thai children with epilepsy aged ≤ 15 y. For individuals having a single steady-state concentration (Css) on one dosage, the Vmax was determined by fixing Km = 4.5 mg/l. For patients with two values for Css with different dosages, the Ludden method was used to determine Vmax and Km. Influences on Vmax and Km by demographic factors including age, sex, weight, serum albumin, and the use of CYP2C9 inducers (carbamazepine, phenobarbital, folic acid, and vigabatrin) and inhibitors (valproic acid and topiramate) were determined by linear mixed-effects regression.
 Results: The majority of patients had sub-therapeutic plasma concentrations of phenytoin. The Vmax and Km were estimated to be 9.84 mg/kg/d and 2.32 mg/l, respectively. Age and weight significantly influenced Vmax, whereas Km had no significant influencing factors.
 Conclusion: The Vmax estimated in this study is different from other populations previously reported. Our results suggest that increased phenytoin dosages may be required to achieve optimal concentrations due to the sub-therapeutic concentrations reported here. The results from this study are beneficial for phenytoin dosage individualization in Thai children.
Highlights
Phenytoin is the anti-epileptic drug of choice for both generalized and partial seizures in children [1]
Small changes in the dosing of phenytoin may result in disproportionately large changes in plasma concentrations
Plasma concentrations below the therapeutic window may lead to treatment failure, while concentrations above may result in toxicity
Summary
Several factors have been identified to impact the variability of these parameters, including age, sex, weight, serum albumin, and drugs that either induce or inhibit the activity of the enzyme CYP2C9 [3,4,5,6,7,8,9,10]. The values of Vmax and Km, as well as any factors influencing them, have never been studied in a population of Thai children. This study aimed to determine Vmax and Km in Thai children with epilepsy and identify the impact of factors on these pharmacokinetic parameters.
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